All cell surfaces are coated with carbohydrates that contain structural information used in recognition processes. These interactions play unique roles in health and disease and represent a relatively untapped source of novel therapeutics. Complex carbohydrates however lack drug-like properties. Our approach is to rationally design small molecule mimics of functional carbohydrates. The bioactive conformation of the functional carbohydrate is determined by both NMR (transfer NOE and STD) and x-ray crystallography. Stabilizing the bioactive conformation (reducing entropy) and searching for second site interactions (increasing enthalpy) increases the specificity and affinity by several orders of magnitude. GMI-1271 (uproleselan) is a specific and potent (K<sub>D</sub> = 450nM) E-selectin antagonist now in phase 3 clinical trials for the treatment of acute myelogenous leukemia (AML). The critical bioactive conformation of stacking the fucose under the galactose is stabilized by incorporating an ethyl group off the cyclohexyl. Replacements for the sialic acid and correct orientation of its carboxyl group dramatically increased activity. Most AML cells express sialyl Lex (E-selectin ligand). The microvasculature in the bone marrow is unique. It constitutively expresses low levels (~10%) of E-selectin. As AML cells enter these protective niches in the bone marrow they bind E-selectin which activates the NFkB pathway and promotes chemoresistance. In our phase 2 study dosing relapsed/refractory AML patients with uproleselan in combination with standard chemotherapy (MEC) broke this chemoresistance. Patients expressing high levels of sialyl Lex (&gt;10%) dosed with uproleselan survived significantly longer (12.7 months) than patients expressing low levels (&lt;10%) of sialyl Lex (5.2 months). Based on strong phase 2 data, the FDA granted uproleselan “Breakthrough Therapy Designation”. Our other glycomimetic drug currently in clinical trials, GMI-1359 was designed to bind both E-selectin and the chemokine receptor, CXCR4. For solid tumors such as breast cancer, E-selectin is a gate keeper that allows tumor cells into the bone marrow. CXCR4 is located in the endosteal region and binds the cells where they remain dormant and are a cause for relapse. Animal models of bone metastasis treated with GMI-1359 show significant improvement in survival, reduction of tumor volume and well as improved integrity of the bone. GMI-1359 is now in phase 2 clinical trial for treatment of breast cancer.

Rational design of glycomimetic drugs in clinical trials for acute myelogenous leukemia and breast cancer

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.